Pyrimidine compounds



Patented Dec. 30, 1947 UNITED STATES PATENT OFFICE PYRIMIDINE COMPOUNDS Great Britain N Drawing.

Application September 1, 1944,

Serial No. 552,382. In Great Britain April 6,

2 Claims. (Cl. 260-251) This invention relates to new pyrimidine compounds and to processes for manufacturing the same. The said new compounds, which will be more closely defined hereinafter, may be described broadly as pyrimidines bearing in the 2- position an arylamino group free from acidic substituents, in the 4-position a hydroxy group and in the 6-position a hydrocarbon radical. They are useful as intermediates in the manufacture of chemotherapeutic agents and particularly of the antimalarial agents of copending applications Serial Nos. 537,536 and 552,383.

It is an object of this invention to provide new pyrimidine compounds. A further object is to provide processes for making the same. A further object is to provide new intermediates for chemotherapeutic agents and processes for making the same. Further objects will appear hereinafter as the description proceeds. These and other objects are achieved by the following invention.

The said new compounds are 4-hydroxy-pyrimidines of the formula ei- Am-C CH N-C-OH wherein X stands for a hydrocarbon radical and Am stands for an arylamino group which may be unsubstituted or may bear one or more simple non-acidic substituents such, for example, as halogen atoms, nitro groups, hydrocarbon radicals (which themselves may optionally bear simple substituents and which may be attached to the arylamino group directly or through an imino, sulphonyl or carbonyl group), alkoxy groups, alkylmercapto groups, cyano groups or esterified carboxyl groups.

According to the invention we make the said new compounds by a process comprising the interaction of the appropriate arylamine with a 4- hydroxy-pyrimidine substituted in the 6-position by a hydrocarbon radical and in the 2-position by an alkylmercapto or substituted alkylmercapto group.

The reaction is conveniently brought about by heating the reagents together, optionally in the presence of a solvent or diluent, whereupon the alkylmercaptan is eliminated and the new 2- arylamino-4-hydroxy-6-substituted-pyrimidine is formed.

The reagents are not necessarily used in stoichiometric proportions. Frequently when the arylamine concerned is readily available and of suitable melting point we use an excess thereof as a solvent or diluent. In other cases we use a slight excess of the amine (usually 1.2 molecular proportions) together with an inert organic solvent such as B-ethox'y-ethanol. But these proportions are a matter of convenience; the reaction will go quite satisfactorily with the stoichiometric proportions or in presence of an ex cess of either reagent.

The starting materials, namely the 4-hydroxypyrimidines bearing in the 6-position a hydrocarbon radical and in the 2-position an alkylmercapto or substituted alkylmercapto group may conveniently be made by interaction of appropriate alkyl isothioureas with formylacetic esters substituted by hydrocarbon radicals on the fl-carbon atom, or by direct S-alkylation of the 6 substituted 2 mercapto 4 hydroxypyrimidines, themselves obtained from thiourea and the appropriate formylacetic esters substituted by hydrocarbon radicals on the p-carbon atom.

As examples of suitable mercapto compound there may be mentioned 2-methylmercapto-4- hydroxy 6 methylpyrimidine, 2 methylmercapto 4 hydroxy 6 ethylpyrimidine and 2- methylmercapto 4 hydroxy 6 phenylpyrimidine; also the corresponding 2-ethylmercapto and 2-benzylmercapto compounds may be used.

As examples of suitable arylamines there may be mentioned aniline, o, mand p-chloroanilines, oand p-methoxyanilines, 0-, mand p-toluidines, oand p-bromoanilines, p-methylmercaptoaniline, 2:4-, 3:4- and 2:5-dichloroanilines, 3:4- and 3:5-dimethylanilines, 2-methyl-4-chloroaniline, 3-chloro-4-methylaniline, 3:5-dibromoaniline, 4-dimethylaminoaniline, p-nitroaniline, p-cyanoaniline, p-carbomethoxyaniline, pethoxyaniline, p-n-butylaniline, p-phenylaniline, ocand p-naphthylamines, 4-chloro-a-naphthylamine, G-brOmO-p-naphthylamine and fi-methoxy-fl-naphthylamine.

- The following examples illustrate but do not limit the invention. The parts are by weight.

Example 1 An intimate mixture of 46.8 parts of 2-methylmercapto-4-hydroxy-fi-methylpyrimidine (H. L. Wheeler and H. F. Merriam, Amer, Chem. J., 1903, 29, 475) and 140 parts of p-chloroaniline is heated to -135 C. for 48 hours. Methyl mercaptan is evolved and the mixture, which is at first liquid, gradually solidifies. After cooling, the reaction mixture is ground up and boiled with 400 parts of ethanol. It is then allowed to cool and the 2-p-chloroanilino-4-hydroxy-6-methylmarge pyrimidine is filtered off, washed with ethanol and dried at Gil-65 C.

By crystallisation from p-ethoxyethanol it can be obtained as colourless thick'laminae; M. P. 294 C.

Example 2 46.8 parts of 2-methylmercapto-4 hydroxy 6 methylpyrimidine and 92.25 parts of ri anisi'dineare heated together in 225 parts of boilingp ethoxyethanol for 48 hours. Methyl mercaptan is evolved, On cooling the product which crystallises out is filtered off and washed with ethyl alcohol. The resulting 2-p-anisidine-4-hydroxy- G-methylpyrimidine is already; pure enough for subsequent use in making the @nmranarggem of eopending application Ser. No. 552,382; but; if

desired, it can be obtained completely pure by crystallisation from fi-ethoxyethanol. When pure it melts at 212-213" C. I

In a' similar manner by-usinfg p'-'phenetidine which crystallisedfromdimethyl forniamide'; 'ha-s M. P. 258-259 c. A t

From p amiiiobnzonitrile"there is obtained 2- -cyarioaniiiiidahydr x :6 nie'thylpy'rimidinei; After ory'stallisationfrorii diiiiethyl formamide 'it has M. P. 330 C:

amine 3 An'intimate mixture offldfipartsof'2=rriethyl n ercapto+4-hydroxy-6=methylpyrimidine1 (H. L. Wheeler andH; F Merriam; Amer. Chem. J 1903;

29', 475) and 140 parts of I d=naphthylamine is- 50 qc 'h r heated to'130'-'135 C; for24'hours; M'ethylmere captairisevolved; After cooling'the reaction'mixture is groundupandthen boiled with"600'parts* of ethanol for 3hours;' It'is'then allowed tocool and the 2-}3-naphthylamino-4-hydroxy-6- methylpyrimidineisfiltered off; washed with ethanol'anddried at '60-65 C.

By crystallisation from fl ethoxyet-hanol it can be obtained as colourlessneedles, M.-P. 243245-' In a'similar way,,by using instead'of d-naphthylamine, -naphthylamine or 4-chloro-a-naph-' thylamine and heating f or 88 hours there is obtained, respectively; 2'-d-naphthylamino-4-hydroxy-fi-ni'ethylpyrimidine of M. P. 256257 C. or 2-(4"-ch1oro-1'-naphthylamino)'- 4 hydroxy 6- methylpy'rimidine of M. P. 298-301'C.

Example-'4 A mixture of 23.4 parts of 2-methylmercapto i-hydroxy-finethylpyrimidine, 41 ,6 parts of 6 bronro -2-naphthylarnine and 110 parts J of 13- ethoxyethanol is stirred and heated at 150-160 er fiqh i Me l merca tan' i o d nda solid separates out.

20 instead of p-a'nis idin'e there" is obtained 2-p- 4 filtered off and washed, first with p-ethoxyethanol and then with ethanol and is then crystallised from fl-ethoxyethanol. 2-(6-bromo-2-naphthyl'amino) 4' hydroxy' 6"- niethylp'yrimidine is thus obtaindas 'oolourlessorystals; MI P. 286- 288 C.

Example 5 A 'rniirtur of 16.6 parts of 2-methylmercapto- 4*-hydroxy fi methylpyrimidine, 23 parts of 6- 'stllled and heated at 150-160 C. h are; Methylmercaptan is evolved and a atesoi'l't. After cooling, the solid is r-filtered oifywashd with ethanol and recrystallis'd fronr-B ethoxybthanol. 2(6-methoxy-2'- naphthyamino) 4 -hydroxy-G-methylpyrimidine is t hus obtained as colourless crystals, M. P. 238 233? C.

Examplef-fi 3 2 l-iiai'tj of a iiitii ifiiereaiiton-riyd oxyw' rriethylr'ryrifiridiriandffi5 fiartsof 2 4-dieh1or'ani line are heatd"tbg etlier*in '751oart's of bomngeethoky'ethanol for re-Hearst iwret yi mercabtan" is evolved: on} choir-egg the-product which "sea a'rates out is filtered off and ivvjalslfi'ed with ethyl a-lcoh'oli- Tlfe -r'sul tiiig 2-(2f-i4 -dichloranilino') a-hydroiyifiiiiiethyl'riyri e-- is already sure enough rbr aaseaeeae u's aging the and malarial "ge ts o'fober idin'gfapiili'eationser; No. 552,383 bu ifdesired; it 'cfar'i seqbtemed nm many: 'i'i'ii'e byerstaliisatiorifrond i -assaye'thanol-i Whe niiie 'it melt's at Wil -280 h M Similarly, from ase aihi roaniiinethere isobjmethylpyrimidine of M. P. 244246 C.

Eairivt'pzf 31 parts of 2-methylmercapto-4-hydroxy-6- '15 methylpyrimidine arid 57 parts of 5-ch1oro-otoluidine (i. e. 2-me"thyl -4=chloroaniline) are heated together in '75- parts of boiling p-ethoxyethanol for 48 hours. Methylv rnercaptan. is evolved. eastern liefriroduct whiehicfystah err 'andjwssliedr with ;;emyr The "res ting" '2-(2' rnethyl 4 chldiio? serjlil or5fi2j383but fdesir'ed' *caa-beeb ames adamantly pilr'e by amsanon mare-anew: ethanol. w enuit flm'eltsat 25 T 'f In 'a sihiilar manner, 5y using-s murai: rnethylaniline instead of neamethy 4= A: mixture of '23-.4Ipar ts of 2 methylr'neicapto-- 4-hydroxy-6-methylpyrimidine and 47.9 parts oi m 'chloroariiline is' heated to 1-30-4355" G; for 48 hours andistirred asdong-asthairisfeasiblei The reaction; mixture gradually solidifies during: the course of the reaction and-"methylmercaptan- 1'sevolved. After cooling, thereaction mixture is broken up and boiled with 200 parts of ethanolfor; 2; hours.- Itis-then allowed: to-cool and the '-hl9r n in Ashrams!-fi methylprri i-i n risfilisr d'pfi shed w i nd' dried.-

After cooling, the solid is .75 at 60-65 C. It is sufiiciently pure at this stage Example 9 15.6 parts of Z-methylmercapto-4-hydroxy-6- methylpyrimidine and 20.5 parts of aniline are heated together in 50 parts of boiling ,B-ethoxyethanol for 48 hours. Methylmercaptan is evolved and some of the product separates from solution during the reaction. The mixture is then cooled and the 2-anilino-4-hydroxy-G-methylpyrimidine is filtered off, washed with ethanol and dried at (ill-65 C. After crystallisation from B-ethoxyethanol it has M. P. 244246 C.

Example 32 parts of 2-methylmercapto-4-hydroxy-6- methylpyrimidine and 50 parts of 3:4-dimethylaniline are heated together in 75 parts of boiling p-ethoxyethanol, with stirring, for 48 hours. Methyl mercaptan is evolved. On cooling 2- (3 :4 dimethylanilino) 4 hydroxy-G-methylpyrimidine crystallises out and is filtered off and washed with ethanol. It is already pure enough to be used forthwith in making the antimalarial agents of copending application Ser. No. 552,383 but if desired can be obtained quite pure by crystallisation from B-ethoxyethanol; it then melts at 238239 C.

In a similar way, by using 3:5-dimethylaniline instead of the 3:4-dimethylaniline of the above example, there is obtained 4-hydroxy-2-(3':5- dimethylanilino)-6-methy1pyrimidine of M. P. 268 C.

Example 11 15.6 parts of 2-methylmercapto-4-hydroxy-6- methylpyrimidine and 30 parts of 3:5-dibromoaniline are heated together in 140 parts of boiling ,B-ethoxyethanol for 48 hours. Methylmercaptan is evolved. After cooling 2-(3:5'-dibromoanilino) -4-hydroxy 6 methylpyrimidine which has separated out is filtered off. It is purified by boiling with a small quantity of fi-ethoxyethanol for about 5 minutes, filtering, washing with ethanol and drying at 60-65" C. It is thereby obtained as practically colourless needles, M. P. 325 C.

Example 12 31.2 parts of 2-methylmercapto-4-hydroxy-6- methylpyrimidine and 61.5 parts of o-anisidine are mixed and heated together at 125-130 C. for 48 hours with occasional stirring. The evolution of methyl mercaptan which at first is brisk is by that time only slight. After cooling, the reaction mixture is ground up and boiled with 200 parts of ethanol for 3 hours. It is then allowed to cool, and the 2-(2'-methoxyanilino)- 4-hydroxy-6-methylpyrimidine which has separated out is filtered off, washed with ethanol and dried at 60-65 C. By crystallisation from p-ethoxyethanol it is obtained as colourless needles, M. P. 245-246 0.

Example 13 31 parts of 2-methylmercapto-4-hydroxy-6- methylpyrimidine and 93 parts of o-toluidine are stirred together at 130-135 C. for 48 hours. Methyl mercaptan is evolved and the reaction mixture slowly solidifies. After cooling it is ground up and refluxed for 3 hours with 250 parts of ethyl alcohol. It'is then cooled, and the crystals which separate out are filtered off and dried. There is thus obtained 2-(2-methylanilino)-4- hydroxy-G-methylpyrimidine. It is sufficiently pure to be used forthwith in making the antimalarial agents of copending application Ser. No. 552,383 but if desired may be purified by crystallisation from 3-ethoxyethanol. It has M. P.

In a similar manner by using m-toluidine instead of the o-toluidine of the above example there is obtained 4-hydroxy-2-(3-methylanilino) -6-methylpyrimidine of M. P. 212-213 C.

Example 14 32 parts of 2-methylmercapto-4-hydroxy-6- methylpyrimidine and 54.4 parts of p-dimethylaminoaniline are heated together in parts of boiling fl-ethoxyethanol for 24 hours. Methyl mercaptan is evolved. On cooling, the product which crystallises out is filtered oil and washed with ethanol. The 2- (4'-dimethylaminoanilino) 4-hydroxy-G-methylpyrimidine so obtained is pure enough to be used forthwith in making the antimalarial agents of copending application Ser. No. 552,383 but may. if desired, be obtained quite pure by crystallisation from fl-ethoxyethanol. It then has M. P. 240-242 C.

Example 15 An intimate mixture of 8.2 parts of z-methylmercapto 4 hydroxy 6 phenyl pyrimidine (Wheeler and Merriam, Am. Chem. J., 1903, 29, 490) and 12 parts of p-chloroaniline are heated together in an oil bath maintained at -140 C. for 6 hours. Methyl mercaptan is evolved and the mixture, which is at first liquid, solidifies. After cooling it is ground up and boiled with 75 parts of ethanol. The mixture is then cooled and the 2-p-chloroanilino-4-hydroxy-fi-phenyl-pyrimidine is filtered off, washed with ethanol and dried at 100 C.

By crystallisation from p-ethoxyethanol it can be obtained in colourless needles of M. P. 312- 313 C.

Example 16 An intimate mixture of 31.2 parts of 2-methylmercapto-4-hydroxy-G-methylpyrimidine (H. L. Wheeler and H. F. Merriam, Amer. Chem. J., 1903, 29, 475) and 93.6 parts of p-toluidine is eated to ISO- C. for 48 hours with stirring as long as that is feasible. Methyl-mercaptan is evolved and the mixture which is at first liquid, gradually solidifies. After cooling, the reaction mixture is ground up and boiled with 400 parts of ethanol. It is then allowed to cool and the 2- p-toluidinol-hydroxy 6 methylpyrimidine is filtered off, washed with ethanol and dried at 60-65 C.

By crystallisation from p-ethoxyethanol it can be obtained as colourless crystals, M. P. 230 C.

Example 17 31.2 parts of 2-methylmercapto-4-hydroxy-6- methylpyrimidine and 55.6 parts of 4-methy1- mercaptoaniline are heated together in '75 parts of boiling p-ethoxyethanol for 48 hours. Methylmercaptan is evolved. On cooling 2-p-methylmercapto-aniline-4-hydroxy-6-methyl pyrimidine crystallises out and is filtered off, Washed with ethyl alcohol and dried. After crystallisation from fi-ethoxyethanol it has M. P, 210 212 C.

I Exanizple 18 3112 parts of 2 methylmercapto 4 hydroxy fimethylpyrimiclineand -93 1 parts of p-nitroaniline areintimately mixed and heated at 140 -150 C. for 48 hours. The mixture,which at first is liquid'gradually solidifies. After cooling, the-reactionmixture is groundup-and boiled with'300 parts of ethanol. The solution is filtered-hot and the residue, which is 2-p-nitroanilino-4-hydroxy-fi-methylpyrimidine, is washed withetha- 1101 and dried. It may be further purifiedflf de- 'sired,-by dissolvingit in sodiumhydroxide solution and reprecipitating "with acetic acid. The melting point isabove 300 0.

Whereas the above description and'examples illustrate many widely -.va,rie,d embodiments of the invention it will be apparent to one skilled in the art that 'many otherem-budiments andvariations may bedevised without departing from the spirit and scope thereof, and accordingly it is-to be {understood that the invention is not in any :way limited except as defined in the following claims.

'We claim:

,1. As a new compound, -4--hydroxy-6-methyl- 2Q(rifichloroanilino): yr m d ne. vcon-1?,. l'mrldin 7:2. 11 pyrimidine :compound corresponding .to theformula N=C--.-QH

whereinQ is a phenyl radical hearing atleast -REFERENCES CITED The following references are of record'in-the file of this patent:

GhemicalReviews-vol. 13, October 1933, No. 2;

35 pp. 246, 226,248, and 249. 

